The impact of alcohol-induced ATF6-mediated ER stress and Golgi disorganization on pro-metastatic glycosylation of integrins in prostate cancer

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Abstract The link between prostate cancer (PCa) risk and alcohol consumption has long been debated. We recently found in an extensive assessment of the epidemiologic data that, since the onset of the PSA testing era, most studies indicate alcohol consumption is strongly associated with PCa risk. Despite this epidemiologic support, little is known about the underlying mechanisms linking alcohol to PCa risk, progression, and mortality. Dr. Petrosyan introduced the concept of "onco-Golgi," where the Golgi becomes fragmented, resulting in altered glycosylation and trafficking of glycoproteins. Additionally, this Golgi disorganization is linked to activating transcription factor 6 (ATF6)-mediated Endoplasmic Reticulum (ER) stress. This results in increased plasma membrane (PM) expression of αv integrins abnormally glycosylated by Golgi glycosyltransferase, N- acetylglucosaminyltransferase-V (MGAT5). Importantly, these MGAT5-modified integrins form clusters with pentameric Galectin-3, resulting in increased retention on the PM. This, in turn, modulates tumor cell behavior, including adhesion and migration, which promotes prostate tumor dissemination to lymph nodes and distant organs. We have found that ethanol (EtOH) treatment aggravates Golgi disorganization and PCa tissues from heavy alcoholics have higher MGAT5 expression and PM Integrin αv levels. We propose that EtOH promotes PCa lethality by increasing Integrin αv-mediated PCa progression. Altered glycosylation of Integrin αv in the onco- Golgi is expected to be exacerbated by alcohol's disorganizing effect on Golgi. Preliminary data demonstrate a positive correlation between the number of Golgi fragments and the PM intensity of Integrin αv in EtOH-treated docetaxel-resistant PCa cells. Importantly, we have found that PCa Golgi disorganization is autophagy-driven and that the autophagy inhibitor, Hydroxychloroquine (HCQ), restores the compact Golgi in advanced PCa cells. We have also shown that ATF6-mediated ER stress results in expression of underglycosylated, high-Mannose (high-Man) integrins to the PM through ER-PM junctions. Depletion of ATF6 decreases the amount of high-Man integrins on the PM and in ER-PM junctions, as well as reduces the total number of ER-PM communications. We have demonstrated the synergistic effect of Golgi restoration by HCQ and ER stress inhibition by ATF6 depletion in preventing orthotopic tumor growth and metastasis. These exciting data led us to expect that similar combination treatments will decrease the pro-metastatic effects of EtOH administration. We have observed rescued Golgi morphology in cells treated with both EtOH and HCQ, suggesting that Golgiphagy, blocked by HCQ, is involved in EtOH-induced Golgi disorganization. Additionally, HCQ restores the level of PM Integrin αv to that of control cells. We expect that combined HCQ treatment and ATF6 depletion will effectively attenuate the effects of EtOH on PCa aggressiveness and metastasis. Overall, these data will shed light on the previously unknown mechanism of alcohol-promoted prostate tumor growth and metastasis and provide a potentially effective therapeutic strategy.